Information obtained during the past decade suggests the need to reexamine the possibility that the onset of myocardial infarction and sudden cardiac death is frequently triggered by daily activities. The importance of physical or mental stress in triggering onset of coronary thrombosis is supported by the findings that 1) the frequencies of onset of myocardial infarction, sudden cardiac death, and stroke show marked circadian variations with parallel increases in the period from 6:00 AM to noon, 2) transient myocardial ischemia shows a similar morning increase, and episodes are often preceded by mental or physical triggers, 3) a ruptured atherosclerotic plaque, often nonobstructive by itself, lies at the base of most coronary thrombi, 4) a number of physiologic processes that could lead to plaque rupture, a hypercoagulable state or coronary vasoconstriction, are accentuated in the morning, and 5) aspirin and beta-adrenergic blocking agents, which block certain of these processes, have been shown to prevent disease onset. The hypothesis is presented that occlusive coronary thrombosis occurs when 1) an atherosclerotic plaque becomes vulnerable to rupture, 2) mental or physical stress causes the plaque to rupture, and 3) increases in coagulability or vasoconstriction, triggered by daily activities, contribute to complete occlusion of the coronary artery lumen. Recognition of the circadian variation--and the possibility of frequent triggering--of onset of acute disease suggests the need for pharmacologic protection of patients during vulnerable periods, and provides clues to mechanism, the investigations of which may lead to improved methods of prevention.

Circadian variation and triggers of onset of acute cardiovascular disease.

Fish oils and plasma lipid and lipoprotein metabolism in humans: a critical review.

A detailed technical overview summarizes and discusses available evidence concerning the effects of fish oil n-3 polyunsaturated fatty acids (PUFA's) on reducing cardiovascular disease risks. Attention is given to: the characteristics and metabolism of n-6 and n-3 PUFA's and the effects of n-3 PUFA's on plasma lipid profiles; the role of n-3 PUFA's in reducing atherosclerosis risk; possible protection of n-3 PUFA's during myocardial infarction; the relative importance of eicosapentaenoic vs. docosahexaneoic acids; and appropriate intakes of n-3 PUFA's. The potential adverse health effects from ingesting fish oils also are discussed.(wz)

Cardiovascular effects of n-3 fatty acids

The opposing effects of n-3 and n-6 fatty acids

Background Cardiac troponin T is a regulatory contractile protein not normally found in blood. Its detection in the circulation has been shown to be a sensitive and specific marker for myocardial cell damage. We used a newly developed enzyme immunoassay for troponin T to determine whether its presence in the serum of patients with unstable angina was a prognostic indicator. Methods We screened 109 patients with unstable angina (25 with accelerated or subacute angina and 84 with acute angina at rest) for serum creatine kinase activity, creatine kinase isoenzyme MB activity, and troponin T every eight hours for two days after admission to the hospital. The outcomes of interest during the hospitalization were death and myocardial infarction. Results Troponin T was detected (range, 0.20 to 3.64 micrograms per liter; mean, 0.78; median, 0.50) in the serum of 33 of the 84 patients (39 percent) with acute angina at rest. Only three of these patients had elevated creatine kinase MB activity (two were positive for troponin T, and one was negative). Of the 33 patients who were positive for troponin T, 10 (30 percent) had myocardial infarction (3 after coronary-artery bypass surgery), and 5 of these died during hospitalization. In contrast, only 1 of the 51 patients with angina at rest who were negative for troponin T had an acute myocardial infarction (P less than 0.001), and this patient died (P = 0.03). Thus, 10 of the 11 patients with myocardial infarctions had detectable levels of troponin T; only 1 had elevated creatine kinase MB activity. Troponin T was not detected in any of the 25 patients with accelerated or subacute angina, and none of these patients died. Conclusions Cardiac troponin T in serum appears to be a more sensitive indicator of myocardial-cell injury than serum creatine kinase MB activity, and its detection in the circulation may be a useful prognostic indicator in patients with unstable angina.

https://www.nejm.org/doi/pdf/10.1056/NEJM199207163270302

The prognostic value of serum troponin T in unstable angina.

SUMMARY Epidemiologic andexperimental datasuggest an antiatherothrombotic potential ofc-3 polunsaturated fatty acids. Therefore, theWestern diet, whichsupplies predominantly w-6polyunsaturatedfatty acids, was supplemented with40ml/day ofcodliver oil, whichprovides about10g ofco-3 polyunsaturated fatty acids daily, for25daysineight volunteers. Thew-3polyunsaturated fatty acids were incorporated inplatelet anderythrocyte membrane phospholipids attheexpenseofw-6polyunsaturated fatty acids.Bleeding timeincreased (p< 0.01) andplatelet count(p< 0.05), platelet aggregation upon ADPandcollagen (p< 0.01-0.05), andassociated thromboxane B2 formation (p< 0.01) decreased. Blood pressure(p< 0.05) andblood pressureresponsetonorepinephrine (p< 0.01) andangiotensin II(NS)fell, without majorchanges inplasma catecholamines, renin, urinary aldosterone, kallikrein, prostaglandins E2 andF2, andredcell cation fluxes. Biochemical andfunctional changes werereversed 4weeks after codliver oilwasdiscontinued. Formation ofprostaglandins derived fromeicosapentaenoic acid andinterference of eicosapentaenoic acidwithformation andaction ofprostaglandins derived fromarachidonic acid were evident invitro. Whatever themechanism, this moderate supplement ofw-3polyunsaturated fatty acids markedly changed membranephospholipids, which wasassociated with ashift toward less reactive platelets anda blunted circulatory responsetopressurehormones. SEVERALindependent lines ofevidence suggest a protective potential ofdietary eicosapentaenoic acid (all cisC20:5cw3) against cardiovascular disease. Greenland Eskimos and, toalesser extent, someJapanese, haveahighdietary intake oflong-chain co-3 polyunsaturated fatty acids fromseafood' andalow

Platelet function, thromboxane formation and blood pressure control during supplementation of the Western diet with cod liver oil.

Biochemical evidence of platelet activation in patients with persistent unstable angina.

To study the possible role of catecholamines in platelet activation, platelet aggregation stimulated by ADP, collagen, arachidonic acid and L-epinephrine, thromboxane B2 (TXB2) formation and plasma levels of catecholamines and renin were studied in healthy men both before and after 6 days of propranolol treatment (40 mg three times daily) under control conditions and during sympathoadrenergic stimulation by physical exercise (200 W) or smoking Exercise markedly increased plasma norepinephrine from 128 +/- 28 to 998 +/- 418 pg/ml (+/- SD), and plasma renin activity from 10 +/- 05 to 42 +/- 18 ng AI/ml  hour Smoking predominantly increased plasma epinephrine, from 47 +/- 25 to 154 +/- 76 pg/ml Propranolol did not consistently influence these variables, but blunted the circulatory response to exercise and smoking Despite the marked increases of plasma catecholamines after both stimuli with and without beta blockade, platelet aggregation stimulated by ADP, 1-epinephrine, collagen and arachidonic acid and associated TXB2 formation were not enhanced Moreover, as already suggested by a trend toward reduced aggregability in these settings, plasma norepinephrine levels in the same range (745 +/- 368 pg/ml) due to infusion (5 micrograms/min) significantly reduced platelet aggregation with low-dose collagen (025-075 micrograms/ml), I-epinephrine (02-10 microM) and ADP (05-15 microM) These data do not support a role of endogenous catecholamines in initiating platelet activation and TXB2 formation

Plasma catecholamines, platelet aggregation and associated thromboxane formation after physical exercise, smoking or norepinephrine infusion.

The conversion of dietary eicosapentaenoic acid to prostanoids and leukotrienes in man.

BACKGROUND It was the purpose of this study to determine the effects of the combination of aspirin (ASA) and fish oil, which is rich in n-3 polyunsaturated fatty acids, on the eicosanoid profile of patients with coronary artery disease. Specifically, we wanted to determine whether the ASA-induced reduction in prostacyclin production is due to inhibition of endothelial cell cyclooxygenase or to reduced endoperoxide shift from platelets and whether ASA negates the potentially beneficial effects of fish oil on the eicosanoid profile. METHODS AND RESULTS Fourteen patients with clinically stable but advanced coronary artery disease received 12 g (n = 8) or 16 g (n = 6) of fish oil concentrate containing 6 or 8 g of n-3 fatty acids for 6 weeks. In addition to the fish oil, patients received increasing daily doses of ASA (50 mg, 100 mg, 325 mg, and 1,300 mg; the latter in four divided doses). Each dose was taken for 2 weeks. With fish oil supplementation, red blood cell phospholipid fatty acid content of arachidonic acid (AA) decreased and of eicosapentaenoic acid (EPA) increased so that EPA as a percent of AA increased from 2% to 26%. Serum thromboxane B2, which represents the production of TXA2 by maximally stimulated platelets, was suppressed by 38% on fish oil alone and by 97% or greater on all doses of ASA. Excretion of PGI2-M, the main urinary metabolite of PGI2 (derived from AA), fell from 50 +/- 4 ng/g of creatinine to 42 +/- 2 ng/g on fish oil alone (p = 0.02). On 50 mg of ASA per day, PGI2-M excretion was 26 +/- 2 ng/g of creatinine (p less than 0.001 versus fish oil alone). On 100 mg and 325 mg of ASA per day, PGI2-M was 24 +/- 3 ng/g and 27 +/- 3 ng/g, respectively (p V NS versus value on 50 mg per day). PGI3-M, the main urinary metabolite of PGI3 (derived from EPA), increased from 0.2 +/- 0.1 ng/g of creatinine to 4.9 +/- 0.7 ng/g on fish oil alone (p less than 0.001). In contrast with the marked ASA-induced decline in PGI2-M, PGI3-M excretion was not affected by the addition of ASA, even at the higher doses (4.6 +/- 0.7 ng/g and 4.9 +/- 0.5 ng/g on 325 mg per day and 325 mg four times daily, respectively). CONCLUSIONS Moderate-dose (325 mg per day or less) ASA taken once daily has no effect on PGI3 production despite significantly reducing PGI2 production. This suggests that endothelial cell cyclooxygenase is minimally inhibited by such doses of ASA and that a large percent of the PGI2 produced in patients with advanced coronary artery disease derives from the transfer of prostaglandin endoperoxides from activated platelets to endothelial cells. The loss of these substrates accounts for the decrease in PGI2 with moderate-dose ASA. Thus, the ASA-induced decrease in PGI2 may in large part be an unavoidable consequence of ASA-induced platelet cyclooxygenase inhibition. ASA does not negate the potentially beneficial effects of n-3 fatty acids on the eicosanoid profile.

Aspirin-induced decline in prostacyclin production in patients with coronary artery disease is due to decreased endoperoxide shift. Analysis of the effects of a combination of aspirin and n-3 fatty acids on the eicosanoid profile.

Reinhard Lorenz

Papers

Platelet function, thromboxane formation and blood pressure control during supplementation of the Western diet with cod liver oil.

Biochemical evidence of platelet activation in patients with persistent unstable angina.

Plasma catecholamines, platelet aggregation and associated thromboxane formation after physical exercise, smoking or norepinephrine infusion.

The conversion of dietary eicosapentaenoic acid to prostanoids and leukotrienes in man.

Aspirin-induced decline in prostacyclin production in patients with coronary artery disease is due to decreased endoperoxide shift. Analysis of the effects of a combination of aspirin and n-3 fatty acids on the eicosanoid profile.